胰高血糖素受体及胰高血糖样肽-1受体双重激动剂ZP2495：一药双靶治疗糖尿病合并心脏缺血再灌注损伤

Diabetes is associated with 2-4 times increased risk of cardiac mortality compared with patients without diabetes. Reducing the cardiac mortality in patients with diabetes is an essential way to improve the prognosis of diabetic patients accompanied by coronary artery disease. Previous studies have demonstrated that diabetes led to reduced aerobic oxidation of glucose and decreased ATP generation. Furthermore, cardiac ischemia-reperfusion (I/R) injury also led to reduced glucose decomposition which aggravated the dysfunction of myocardial cellular energy metabolism. The glucagon receptor and glucagon-like peptide -1 (GLP-1) receptor dual agonist ZP2495 could moderate insulin resistance and enhance cardiac function by improving the cardiomyocyte energy metabolism. Thus, ZP2495 may reverse the un-balancing pathological metabolic state of ischemic cardiac myocardium. However, the effects and mechanisms of ZP2495 on the I/R injury as well as the energy metabolism state in the diabetic mice are not well understood. Diabetes accompanied by cardiac I/R injury model will be constructed in this project. The effects and mechanism of ZP2495 on diabetes accompanied by cardiac I/R injury will be investigated both in vivo and in vitro. The present project will further help reveal the new target in the treatment of diabetes accompanied by cardiac I/R injury.

糖尿病患者的心源性死亡率比非糖尿病患者高2-4倍。研究表明，糖尿病导致葡萄糖有氧氧化减低，ATP生成减少，而心脏缺血再灌注（I/R）损伤也导致葡萄糖分解减低，加剧心肌细胞能量代谢异常。胰高血糖素受体及胰高血糖样肽-1（GLP-1）受体双重激动剂ZP2495，能够在改善胰岛素抵抗动物模型缺血心肌细胞能量代谢的基础上改善心脏功能，逆转缺血心肌能量供需不平衡的病理状态。然而，ZP2495能否降低糖尿病小鼠的心脏缺血再灌注损伤？其逆转糖尿病状态下缺血心肌能量供需异常，改善心脏功能的具体分子机制是什么？目前尚不清楚。我们拟构建糖尿病伴心脏缺血再灌注损伤小鼠模型，从整体、细胞、分子水平揭示胰高血糖素受体及GLP-1受体双重激动剂ZP2495在糖尿病合并心脏缺血再灌注损伤中的作用及下游分子机制。本项目将有助于进一步揭示糖尿病合并心脏缺血再灌注损伤保护的新靶点，为该疾病的防治提供新的思路。

本项目验证了 “胰高血糖素受体及胰高血糖样肽-1（GLP-1）受体双重激动剂ZP2495降低糖尿病状态下的心脏缺血再灌注损伤，其机制与降低心肌细胞凋亡指数，减轻心肌细胞线粒体损伤，改善心肌细胞线粒体生物合成相关”这一科学假设。项目团队结合离体、在体实验，采用抑制剂阻断及基因干预后发现：① ZP2495显著提高db/db小鼠心脏缺血再灌注损伤后心功能，改善心肌葡萄糖代谢，降低心肌梗死面积。② ZP2495降低db/db小鼠心脏缺血再灌注损伤后心肌细胞线粒体损伤，升高高糖诱导乳鼠心肌细胞模拟缺血再灌注损伤后心肌细胞线粒体膜电位，减少心肌细胞线粒体细胞色素C释放，减少心肌细胞线粒体ROS生成。③ZP2495治疗糖尿病合并心脏缺血再灌注损伤是通过修复受损的线粒体发挥保护作用这一过程与Akt/FoxO3a 及AMPK/FoxO3a通路的激活有关。本项目研究提示，糖尿病合并心脏缺血再灌注损伤条件下，心肌细胞能量代谢障碍，ZP2495同时激动胰高血糖素受体和胰高血糖样肽-1受体，增加心肌细胞收缩力的同时改善心肌细胞能量代谢，减轻线粒体损伤，改善线粒体功能，从而降低糖尿病状态下的心脏缺血再灌注损伤。